Novel formulation

ABSTRACT

A new metered unit dose comprising 40 μg or less of budesonide is disclosed as well as a formulation thereof and the use thereof for the treatment of conditions in the nose.

FIELD OF THE INVENTION

[0001] The present invention relates to a new unit dose of budesonide, aformulation thereof, and its use for the treatment of conditions of thenose.

BACKGROUND OF THE INVENTION

[0002] Glucocorticosteroids are widely used for the treatment ofseasonal allergic as well as perennial rhinitis. Intranasalglucocorticosteroids reduce inflammation of the nasal mucosa includingedema. In addition, they are known to suppress the recruitment ofpolymorpho-nuclear and mononuclear cells, cytokine production, and,during maintenance treatment, both early and late-phase nasal reactions.

[0003] One of the glucocorticosteroids known for intranasal use isbudesonide,16α,17α-butylidenedioxy-11β,21-dihydroxypregna-1,4-diene-3,20-dione.

[0004] Initially solid budesonide was used in pressurized metered doseinhaler (pMDI) preparations for intranasal administration, suitablydispensed from a specially adapted nasal inhaler. A recommended maximumdaily metered dose of budesonide has been 400 μg. Later on a nasal spraypreparation for delivery from a spray device was prepared, containingbudesonide in the form of an aqueous suspension. The same maximum dailymetered dose as for the pMDI preparation was recommended. A thirdformulation is a dry powder formulation.

[0005] Both the nasal pMDI inhaler device and the aqueous nasal spraydevice are constructed to dispense a defined unit dose at eachactuation. For example, a metered unit dose of 50 μg has a recommendedadministration regime of one dose per nostril, four times daily,yielding a total of eight 50 μg metered doses per day. Alternatively, ametered unit dose of 100 μg would provide the same total metered dailydose (400 μg) if administered to each nostril twice daily, for a totalof four 100 μg metered doses per day.

[0006] We have now surprisingly found that a lower metered unit dose ofbudesonide than that previously used can be administered safely andeffectively to the nose.

DISCLOSURE OF THE INVENTION

[0007] According to the invention we provide a metered unit dose of atherapeutic composition comprising budesonide in therapeuticallyeffective amount that is less than about 40 μg, said composition beingsuitable for nasal administration to a mammal in a single dose.

[0008] Preferably, the metered unit dose comprises from about 16 toabout 40 μg of budesonide. In a preferred embodiment of the invention,the metered unit dose comprises about 32 μg of budesonide.

[0009] With this new lower metered unit dose, it is possible for thepatient to take a lower metered daily dose, while still maintainingefficacy. The new lower unit dose is also convenient for the patient.Surprisingly, metered daily doses of 256 μg and 400 μg, delivered bynasal spray, were found to be equally efficacious. A metered daily doseof 256 μg can be obtained with a metered unit dose of 32 μg budesonide,dispensed 8 times daily (two doses in each nostril, twice a day).

[0010] A suitable pharmaceutical formulation of budesonide is asuspension of micronised budesonide in an aqueous vehicle.

[0011] Thus, the invention also comprises a unit dose, and preferably ametered unit dose, of a therapeutic composition comprising atherapeutically effective amount of budesonide that is less than about40 μg, wherein the budesonide is in the form of finely divided particlesand is suspended in an aqueous medium, said composition being suitablefor administration to a mammal in a single dose.

[0012] Preferably, the unit dose formulation comprises from about 16 toabout 40 μg of budesonide. In a most preferred embodiment of theformulation, the amount of budesonide is about 32 μg.

[0013] In a further aspect the invention comprises a suspension,preferably an aqueous suspension, comprising from about 0.6 to about 0.7mg/ml (i.e. from about 0.06 to about 0.07% w/w) of budesonide.

[0014] In yet a further aspect the invention comprises a method oftreating conditions of the nose of mammals by administering thereto ametered unit dose of 40 μg or less of budesonide.

[0015] Conditions that can be treated according to the invention include

[0016] seasonal allergic rhinitis, i.e. pollinosis caused by pollensfrom ragweed, birch, grass, ceder or other plants

[0017] perennial allergic rhinitis caused by e.g. dust mites(Dermatophagoides pteronyssinus and D. farinae), cockroaches and mammalssuch as cats, dogs and horses

[0018] perennial non-allergic rhinitis

[0019] nasal polyps, as well as prevention of post surgical nasal polyps

[0020] chronic sinusitis

[0021] recurrent sinusitis.

[0022] In order to form a stable suspension with a minimal tendency toagglomerate or form a sediment, a thickening agent may be included inthe formulation. Examples of suitable thickening agents aremicrocrystalline cellulose, sodium carboxymethylcellulose, xanthan gum,carbomer, guar gum and hydroxypropyl cellulose. The thickening agent maybe present at about 0.1 to 3.0% w/w of the formulation. Preferablymicrocrystalline cellulose and sodium carboxymethyl cellulose arepresent at about 0.5 to 2.5%, xanthan gum at about 0.3 to 3%, carbomerat about 0.1 to 2%, guar gum at about 0.3 to 2% and hydroxypropyl methylcellulose at about 0.5 to 3.0%, w/w of the formulation.

[0023] Agents which make the suspension isotonic may be added. Examplesare dextrose, glycerin, mannitol, sodium chloride and potassiumchloride.

[0024] To obtain an efficient dispersion of the budesonide particles inthe suspension, a surfactant may be used. Examples of suitablesurfactants are Polysorbate 80 (Tween 80) as well as otherpolyoxyethylene sorbitan fatty acid esters, poloxamers, polyoxyethylenealkyl ethers and polyoxyethylene castor oil derivatives. The surfactantmay be present at about 0.005 to 2% w/w of the formulation. We preferthe polyoxyethylene sorbitan fatty acid esters to be present at about0.005 to 0.5%, poloxamers at about 0.01 to 2%, and polyoxyethylene alkylethers or the poiyoxyethylene castor oil derivatives at about 0.01 to1.0%, w/w of the formulation.

[0025] We also prefer the formulation to contain a suitable chelatingagent, e.g. disodium edetate (EDTA). The chelating agent may be presentat about 0.005 to 0.1% w/w of the formulation.

[0026] A preservative agent may be added to protect the formulation frommicrobial contamination. Examples of suitable preservatives arebenzalkonium chloride, methylparaben, propylparaben, potassium sorbateand sodium benzoate. The preservative may be present at about 0.002 to0.5% w/w of the formulation. Preferably benzalkonium chloride is presentat about 0.002 to 0.02%, methylparaben at about 0.05 to 0.25%,propylparaben at about 0.01 to 0.2%, potassium sorbate at about 0.5 to0.2%, and sodium benzoate at about 0.1 to 0.5%, w/w of the formulation.

[0027] The pH of the suspension may be adjusted as required. Examples ofsuitable pH regulating agents are strong mineral acids, e.g.hydrochloric acid. Altematively, the pH of the system can be adjusted bybalancing the acid and salt forms of preservative and chelating agent.We prefer the formulation to have a pH in the range 3.5 to 5.0 and morepreferably from about 4.2 to 4.6.

[0028] The suspension medium is made essentially of purified water (asdescribe in the European Pharmacopoeia and the United StatesPharmacopoeia), e.g. water for injection.

[0029] In the suspension the active constituent budesonide is present assmall particles, where at least 90% of the small particles have a massequivalent sphere diameter of less than 20 μm, preferably at least 80%less than 10 μm and most preferably at least 80% less than 7 μm.

[0030] The new unit dose can suitably be dispensed from the abovementioned specially adapted nasal inhaler or spray device. Other meansfor administration include a simple drop pipette or a rhinyl.Pre-compression metered-dose spray pumps with dose volumes from 25 μl to150 μl can be used, whereby the concentration of budesonide in thesuspension is adjusted to give the desired unit dose of budesonide.Monospray or a bispray pump can be used; for the latter, the recommendedunit dose is sequentially delivered into each nostril, for a totalmetered dose per administration of less than 80 μg budesonide.

[0031] According to a further feature of the invention we also provide atherapeutic method of treating or preventing conditions of the upperrespiratory tract, the method comprising metering into a nostril of amammal a unit dose of budesonide, wherein said metered unit dosecomprises budesonide in a therapeutically effective amount that is lessthan about 40 μg.

[0032] The metered amount of budesonide is preferably less than about320 μg per day, delivered as 8 or more unit doses each dose comprisingbudesonide in an amount that is less than about 40 μg.

[0033] According to a yet further feature of the invention we provide acontainer containing budesonide and adapted to deliver a unit dose or aformulation according to the invention.

[0034] The invention will now be described more in detail in thefollowing non-limiting examples.

EXAMPLE 1

[0035] A unit dose comprising a suspension of 32 μg budesonide in waterwas prepared by mixing the following ingredients: Ingredient (mg)Budesonide, micronised 0.032 Microcrystalline cellulose and 0.625carboxymethylcellulose Sodium (Avicel) Dextrose, anhydrous 2.375Polysorbate 80 0.008 Edetate disodium 0.005 Potassium sorbate 0.060Hydrochloric acid to pH 4.5 Purified water to 50 μl (approx. 47.9 mgadded)

EXAMPLE 2

[0036] A 200 litre bulk suspension, which corresponds to approximately23,000 containers with 120 doses (32 μg/dose) of budesonide each, wasprepared by mixing the following ingredients: Ingredient Amount (kg)Budesonide, micronised 0.128 Microcrystalline cellulose and 2.500carboxymethylcellulose Sodium (Avicel) Dextrose, anhydrous 9.500Polysorbate 80 0.032 Edetate disodium 0.020 Potassium sorbate 0.240Hydrochloric acid to pH 4.5 Purified water to 204.2

1. A metered unit dose of a therapuetic composition comprisingbudesonide in a therapeutically effective amount that is less than about40 μg, said composition being suitable for nasal administration to amammal in a single dose.
 2. A unit dose according to claim 1, comprisingfrom about 16 to about 40 μg of budesonide.
 3. A unit dose according toclaim 1, comprising about 32 μg budesonide.
 4. A unit dose of atherapeutic composition comprising a therapeutically effective amount ofbudesonide that is less than about 40 μg, wherein the budesonide is inthe form of finely divided particles and is suspended in an aqueousmedium, said composition being suitable for administration to a mammalin a single dose.
 5. A unit dose according to claim 4, wherein theamount of budesonide is from about 16 to about 40 μg.
 6. A unit doseaccording to claim 4, wherein the amount of budesonide is about 32 μg.7. The unit dose of claim 4, further comprising one or morepharmaceutically acceptable additives selected from the group consistingof thickening agents, isotonicity agents, surfactants, chealting agents,and preservatives.
 8. The unit dose of claim 4, wherein the massequivalent sphere diameter of the budesonide particles is 10 μm or less.9. A formulation comprising a suspension of about 0.6 to about 0.7 mg/mlof finely divided budesonide in water.
 10. A formulation according toclaim 9, further comprising a pharmaceutically acceptable additiveselected from the group consisting of thickening agents, isotonicityagents, surfactants, chelating agents, and preservatives.
 11. Aformulation according to claim 9, wherein the mass equivalent spherediameter of the budesonide is 10 μm or less.
 12. A formulation accordingto claim 10, wherein the mass equivalent sphere diameter of thebudesonide is 10 μm or less.
 13. A therapeutic method of treating orpreventing conditions of the upper respiratory tract, the methodcomprising administering into a nostril of a mammal a metered unit doseof budesonide, wherein said metered unit dose comprises budesonide in atherapeutically effective amount that is less than about 40 μg.
 14. Amethod according to claim 13, in which the condition to be treated isselected from the group consisting of seasonal allergic rhinitis,perennial allergic rhinitis, perennial non-allergic rhinitis, chronicsinusitis, recurrent sinusitis and nasal polyps.
 15. A therapeuticmethod according to claim 13, wherein the unit dose of budesonide isfrom about 16 μg to about 40 μg.
 16. A therapeutic method according toclaim 13, wherein the unit dose of budesonide is about 32 μg.
 17. Atherapeutic method according to claim 13, wherein the condition to betreated is seasonal allergic rhinitis.
 18. A therapeutic methodaccording to claim 13, wherein the condition to be treated is perennialallergic rhinitis.
 19. A therapeutic method according to claim 13,wherein the condition to be treated is perennial non-allergic rhinitis.20. A therapeutic method according to claim 13, wherein the condition tobe treated is chronic sinusitis.
 21. A therapeutic method according toclaim 13, wherein the condition to be treated is recurrent sinusitis.22. A therapeutic method according to claim 13, wherein the condition tobe treated is nasal polyps.
 23. A therapeutic method of treatingconditions of the upper respiratory tract, the method comprisingmetering into the nose of a mammal a therapeutically effective amount ofbudesonide that is less than about 320 μg per day, delivered as 8 ormore unit doses, wherein each unit dose comprises budesonide in anmetered amount that is less than about 40 μg.
 24. A therapeutic methodaccording to claim 23, wherein the amount of budesonide is about 256 μgper day.
 25. A container containing budesonide and adapted to deliver aunit dose according to claim
 1. 26. A container adapted to administerunit doses of a formulation according to claim 9.